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Page 4 of 5 Orsucci et al. Neuroimmunol Neuroinflammation 2018;5:7 I http://dx.doi.org/10.20517/2347-8659.2017.67

the great majority of “anti-VGKC” autoantibodies are not directed against the potassium channel subunits
but against three proteins that are complexed with these channels, including the cell-adhesion molecule
[3]
Caspr2 . VGKC-antibodies define neurological conditions that are usually immunotherapy-responsive,
but patients with anti-Caspr2 antibodies could have an increased risk of an underlying tumour and a poor
[3]
prognosis .

Caspr2 antibodies bind to the juxtaparanodal regions of myelinated fibers in brain and peripheral nerve .
[4]
[3,4]
Patients with anti-Caspr2 antibodies may show both peripheral and central nervous system features .
Neuropathic pain may be a significant and rather specific manifestation of anti-Caspr2 autoimmunity;
[5]
hyperexcitability of nociceptive pathways has been implicated . Peripheral neuromuscular hyperexcitability
and pain were the main clinical features in our patient; no clinical or MRI signs of limbic encephalitis were
noted. Additional work is required to explain different clinical phenotypes in patients with autoantibodies
against Caspr2.

Isaacs’ syndrome has been described in combination with other autoimmune disorders , including
[6]
[8]
[7]
myasthenia gravis , or associated with a variety of neoplasms, including thymoma and lymphoma . It
can be diagnosed several years before a neoplasm is discovered . In our case, an extensive screening was
[8]
negative for neoplasms, but revealed a segmental Crohn’s disease (to our knowledge, this is the first report of
this association). Patients with Isaacs’ syndrome [9,10] usually improve after treatment of an underlying cancer
[1]
or with symptomatic treatment, although evidence is based on case reports . Carbamazepine, phenytoin,
[1]
lamotrigine and sodium valproate can be used, if necessary in combination . In patients whose symptoms
[1]
are debilitating or refractory to symptomatic therapy, immunomodulatory therapies should be tried .
There are no trials of long-term oral immunosuppression. Prednisolone, with or without azathioprine
[1]
or methotrexate, has been used in some patients . Single case studies suggest that plasma exchange and
[1]
intravenous immunoglobulins may produce some clinical improvement . Of note, all the case studies
reporting the effects of the above mentioned immunomodulatory approaches predated the discovery of anti-
[3]
Caspr2 antibodies . Therefore, the immunological serotype of these patients was unknown. Further studies
are strongly needed to clarify if the serotype influence the optimal therapeutic approach.

Our report suggests that methylprednisolone 1000 mg/day × 5 days and consecutive tapering followed by
plasma exchange can be effective and well tolerated in patient with Isaacs’ syndrome due to anti-Caspr2
antibodies. Since the incidence of this condition is rare, controlled clinical studies are not likely to be
conducted. Therefore, it is important to report single observations; more cases will be necessary to confirm (or
not) the positive effect of this immunomodulatory schedule in anti-Caspr2 Isaacs’ syndrome.

DECLARATIONS
Acknowledgments
The authors are grateful to Dr. Valeria Calsolaro (Neurology Imaging Unit, Imperial College, London &
Department of Clinical and Experimental Medicine, University of Pisa, Italy) for her language revision.

Authors’ contributions
Prepared the manuscript: Orsucci D
Revised the manuscript: Mazzoni M
Clinically studied the patient: Moscato G, Napolitano A
Performed the electromyographic examinations: Cafforio G
Performed the plasma exchange procedure: Margelli M

Financial support and sponsorship
None.